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At least 19 recordsLinked to original sources

PubMed2006

Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale).

BACKGROUND: Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. RESULTS: In this study, we identified comfrey-induced gene expression profile in the livers of rats. Groups of 6 male transgenic Big Blue rats were fed a basal diet and a diet containing 8% comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay. The animals were treated for 12 weeks and sacrificed one day after the final treatment. We used a rat microarray containing 26,857 genes to perform genome-wide gene expression studies. Dietary comfrey resulted in marked changes in liver gene expression, as well as in significant decreases in the body weight and increases in liver mutant frequency. When a two-fold cutoff value and a P-value less than 0.01 were selected, 2,726 genes were identified as differentially expressed in comfrey-fed rats compared to control animals. Among these genes, there were 1,617 genes associated by Ingenuity Pathway Analysis with particular functions, and the differentially expressed genes in comfrey-fed rat livers were involved in metabolism, injury of endothelial cells, and liver injury and abnormalities, including liver fibrosis and cancer development. CONCLUSION: The gene expression profile provides us a better understanding of underlying mechanisms for comfrey-induced hepatic toxicity. Integration of gene expression changes with known pathological changes can be used to formulate a mechanistic scheme for comfrey-induced liver toxicity and tumorigenesis.

Animal Feed↗

PubMed2005

Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study.

In the treatment of minor blunt injuries several topical drugs are known to have anti-inflammatory and analgesic properties. They represent, however, two fundamentally different major pharmacological therapy approaches: the "chemical-synthetical" and the "phytotherapeutical" approach. The main objective of this trial (CODEC_2004) was to compare the efficacy and tolerability of an ointment of Comfrey extract (Extr. Rad. Symphyti) with that of a Diclofenac gel in the treatment of acute unilateral ankle sprain (distortion). In a single-blind, controlled, randomized, parallel-group, multicenter and confirmatory clinical trial outpatients with acute unilateral ankle sprains (n=164, mean age 29.0 years, 47.6% female) received either a 6 cm long ointment layer of Kytta-Salbe f (Comfrey extract) (n=82) or of Diclofenac gel containing 1.16 g of diclofenac diethylamine salt (n=82) for 7 +/- 1 days, four times a day. Primary variable was the area-under-the-curve (AUC) of the pain reaction to pressure on the injured area measured by a calibrated caliper (tonometer). Secondary variables were the circumference of the joint (swelling; figure-of-eight method), the individual spontaneous pain sensation at rest and at movement according to a Visual Analogue Scale (VAS), the judgment of impaired movements of the injured joint by the method of "neutral-zero", consumption of rescue medication (paracetamol), as well as the global efficacy evaluation and the global assessment of tolerability (both by physician and patient, 4 ranks). In this study the primary variable was also to be validated prospectively. It was confirmatorily shown that Comfrey extract is non-inferior to diclofenac. The 95% confidence interval for the AUC (Comfrey extract minus Diclofenac gel) was 19.01-103.09h*N/cm2 and was completely above the margin of non-inferiority. Moreover, the results of the primary and secondary variables indicate that Comfrey extract may be superior to Diclofenac gel.

Adolescent↗

PubMed2000

The efficacy and safety of comfrey.

Herbal medication has gathered increasing recognition in recent years with regard to both treatment options and health hazards. Pyrrolizidine alkaloids have been associated with substantial toxicity after their ingestion as tea and in the setting of contaminated cereals have led to endemic outbreaks in Jamaica, India and Afghanistan. In Western Europe, comfrey has been applied for inflammatory disorders such as arthritis, thrombophlebitis and gout and as a treatment for diarrhoea. Only recently was the use of comfrey leaves recognized as a substantial health hazard with hepatic toxicity in humans and carcinogenic potential in rodents. These effects are most likely due to various hepatotoxic pyrrolizidine alkaloids such as lasiocarpine and symphytine, and their related N-oxides. The mechanisms by which toxicity and mutagenicity are conveyed are still not fully understood, but seem to be mediated through a toxic mechanism related to the biotransformation of alkaloids by hepatic microsomal enzymes. This produces highly reactive pyrroles which act as powerful alkylating agents. The main liver injury caused by comfrey (Symphytum officinale) is veno-occlusive disease, a non-thrombotic obliteration of small hepatic veins leading to cirrhosis and eventually liver failure. Patients may present with either acute or chronic clinical signs with portal hypertension, hepatomegaly and abdominal pain as the main features. Therapeutic approaches include avoiding intake and, if hepatic failure is imminent, liver transplantation. In view of the known serious hazards and the ban on distributing comfrey in Germany and Canada, it is difficult to understand why comfrey is still freely available in the United States.

Comfrey↗

PubMedDate not supplied

A rapid cleanup method for the isolation and concentration of pyrrolizidine alkaloids in comfrey root.

Preparations from comfrey (Symphytum officinale and S. x uplandicum) root and leaf contain varying levels of the hepatotoxic pyrrolizidine alkaloids (PAs). Reference compounds for comfrey are not commercially available, and there is currently no rapid extraction or analytical method capable of determining low levels in raw materials or as adulterants in commercially available extracts. A solid-phase extraction (SPE) method was developed using an Ergosil cleanup column that specifically binds the PAs. With this method, powdered comfrey root was extracted by sonication and shaking with basic chloroform. The extract was applied to the cleanup column under vacuum, washed with 2 mL acetone-chloroform (8 + 2, v/v) followed by 2 mL petroleum ether to remove excess chloroform. The column was dried under vacuum, and the PAs were eluted with 2 successive 1 mL aliquots methanol. Percent recoveries of the PAs following Ergosil SPE had an overall average of 96.8%, with RSD of 3.8% over a range of 1.0 to 25.0 g extracted in 100 mL. Average precision of the method (n = 3 over 4 extraction concentrations) gave an overall RSD of 6.0% for the 5 alkaloids, with a range of 0.8% (5 g in 100 mL) to 11.2% (25 g in 100 mL). Recovery optimization testing showed that 1.0 g comfrey root extracted in 100 mL yielded the greatest recovery (% dry weight) of the PAs, with an extraction efficiency and accuracy of 94.2%, and RSD of 1.7% (n = 9). The unique properties of the Ergosil cleanup column provide rapid sample cleanup, volume reduction, and concentration of PAs from comfrey extracts, and allow the eluant to be analyzed directly by traditional chromatographic methods.

Chromatography, Liquid↗

PubMed1994

Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.).

The presence of hepatotoxic pyrrolizidine alkaloids in comfrey (Symphytum sp.) and the widespread use of decoctions of this plant as a beverage (herbal tea) are of increasing concern. A method for the extraction and solid-phase concentration and capillary gas chromatographic determination of these alkaloids and their N-oxides in botanical materials has been developed and was applied to eleven comfrey-containing products purchased from retail health-food outlets in the Washington, DC, area during May-June 1989. Nine of the 11 products were found to contain measurable quantities of one or more of the alkaloids, in ranges from 0.1 to 400.0 ppm. Products containing comfrey leaf in combination with one or more other ingredients were found to contain the lowest alkaloid levels. Highest levels were found in bulk comfrey root, followed by bulk comfrey leaf. The species of the bulk material was verified by thin-layer chromatography and other means.

Chromatography, Gas↗

PubMed1993

Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats.

Comfrey, a popular herbal remedy, contains hepatotoxic pyrrolizidine alkaloids and has been implicated in recent human toxicity. Although alkaloids from other plant sources have been extensively researched, studies on the hepatotoxic effects of comfrey alkaloids are scant. The effects of high dose comfrey toxicity have been studied and the present investigation was undertaken to identify changes associated with relatively low dose toxicity. Eight young adult rats were dosed weekly for six weeks with 50 mg/kg of comfrey derived alkaloids. The animals were dissected one week after the last dose and the livers examined by light and electron microscopy. Changes at the light microscopic level showed vascular congestion, mild zone 3 necrosis and loss of definition of hepatocyte cellular membranes. Extensive ultrastructural abnormalities were identified in the form of endothelial sloughing and the loss of hepatocyte microvilli. A striking finding was florid bleb formation on the sinusoidal borders of hepatocytes. Many blebs were shed into the space of Disse and extruded to fill, and sometimes occlude, sinusoidal lumina. Platelets were frequently found in areas of bleb formation. There was evidence of late damage in collagenization of Disse's space. Hepatocyte bleb formation is known to occur under a variety of pathological conditions but there is little to no information in the literature on the effects, if any, of bleb formation on fibrogenesis and the microcirculation and its role in the pathogenesis of liver disease. The pyrrolizidine alkaloids of comfrey may serve as an experimental tool to study the process of bleb formation and the intimate relationship between hepatocyte and sinusoidal injury in the liver.

Animals↗

PubMed2005

Mutagenicity of comfrey (Symphytum Officinale) in rat liver.

Comfrey is a rat liver toxin and carcinogen that has been used as a vegetable and herbal remedy by humans. In order to evaluate the mechanisms underlying its carcinogenicity, we examined the mutagenicity of comfrey in the transgenic Big Blue rat model. Our results indicate that comfrey is mutagenic in rat liver and the types of mutations induced by comfrey suggest that its tumorigenicity results from the genotoxicity of pyrrolizidine alkaloids in the plant.

Alkaloids↗

PubMed2004

Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids.

OBJECTIVES: To determine the relative quantities of two hepatotoxic pyrrolizidine alkaloids, symphytine and echimidine, in teas prepared from comfrey leaves (Symphytum officinale), and to determine the potential contribution of the N-oxide forms of these alkaloids to levels of the parent alkaloids. DESIGN: Comfrey leaves were purchased from three commercial sources and used to prepare tea in a manner consistent with the methods used by consumers. An extraction scheme was devised for extraction of the alkaloids, and a gas chromatographic method was developed to quantify the two major alkaloids, symphytine and echimidine. Recognising that the N-oxide derivatives of these alkaloids have also been identified in comfrey preparations, chemical reduction was applied to determine the total quantities of the alkaloids as free bases and as N-oxide derivatives. RESULTS: The concentration of symphytine and echimidine varied considerably between teas prepared from leaves purchased from the different vendors of plant material. Moreover, a much higher concentration of symphytine was found in the tea when steps were included to reduce N-oxides prior to analysis. The treatment of pure symphytine with hot water did not generate the N-oxide derivative de novo. CONCLUSIONS: Since the pyrrolizidine alkaloids are known to be hepatotoxic, consumption of herbal teas made from comfrey leaves may be ill-advised. The concentration of pyrrolizidine alkaloids in such teas may be underestimated substantially unless the concentration of N-oxides is taken into consideration.

Beverages↗

PubMed2002

[Therapeutic characteristance and tolerance of topical comfrey preparations. Results of an observational study of patients].

AIM: To analyze the anti-inflammatory and analgetic properties of the topical comfrey, preparations Kytta-Salbe f, Kytta-Plasma f and Kytta-Balsam f applied to bruises, sprains and distortions and painful conditions of the muscles and joints. METHOD: A prospective open multicentric observational study complying with paragraph 67(6) of the AMG and involving 162 general practitioners. During the two-week period of observation, the patients received an average of one to three applications of the comfrey preparation per day. All 492 questionnaires were evaluated. Efficacy and tolerability were assessed by both physician and patient. RESULTS: Pain at rest and on movement, as also tenderness, improved in the overall observation group by an average of 45-47%. The duration of morning joint stiffness decreased from 20 minutes initially to 3 minutes. During the course of treatment with comfrey, more than two-thirds of the patients were able to reduce or even discontinue their intake of non-steroidal anti-inflammatory drugs and other specific concomitant medication. In most of the cases, both effectiveness and tolerability were assessed to be excellent or good. CONCLUSION: The results of the study confirm the effectiveness and tolerability of the topical comfrey preparation investigated in the treatment of bruises, sprains and distortions as well as painful conditions affecting muscles and joints.

Administration, Topical↗

PubMedDate not supplied

Hepatic veno-occlusive disease associated with comfrey ingestion.

A 23 year old man presented with hepatic veno-occlusive disease and severe portal hypertension and subsequently died from liver failure. Light microscopy and hepatic angiography showed occlusion of sublobular veins and small venous radicles of the liver, associated with widespread haemorrhagic necrosis of hepatocytes. The patient had been on a predominantly vegetarian diet and, prior to his illness, took comfrey leaves which are known to contain hepatotoxic pyrrolizidine alkaloids. Comfrey is widely used as a herbal remedy, but so far has only been implicated in two other documented cases of human hepatic veno-occlusive disease. A possible causal association of comfrey and this patient's veno-occlusive disease is suggested by the temporal relationship of the ingestion of comfrey to his presentation, the histological changes in the liver and the exclusion of other known causes of the disease.

Adult↗

PubMedDate not supplied

Comfrey: assessing the low-dose health risk.

The regular use of comfrey as part of the diet or for medicinal purposes may be a potential health risk as a result of the presence of naturally-occurring pyrrolizidine alkaloids. The majority of these alkaloids are hepatotoxic in both animals and humans, and some have been shown to induce tumours in experimental animals. In this article, the toxic properties of pyrrolizidine alkaloids are reviewed briefly, with particular reference to their presence in comfrey. The acute and long-term health risks at the normally-low levels of comfrey consumption are evaluated and discussed. On the basis of the data that are available currently, the small but significant long-term risk that is associated with the consumption of comfrey justifies the need to limit its intake. This is being achieved by controls under various state Poisons Acts, but also requires further education on the potential dangers of naturally-occurring chemicals of plant origin.

Allantoin↗

PubMed2004

Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.

Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey.

Adolescent↗

PubMed2004

Simultaneous analysis of hepatotoxic pyrrolizidine alkaloids and N-oxides in comfrey root by LC-ion trap mass spectrometry.

The purpose of the current study was to develop a LC-MS(n) method for the analysis of pyrrolizidine alkaloids (PAs) in comfrey. Published data presents an extensive list of PAs and their N-oxides present in comfrey. However, standards are not commercially available for any of the PAs typically present in comfrey. Those PAs that are not stereoisomers were readily resolved on a C(18) column using a water-acetonitrile gradient as the mobile phase. The use of a selective technique, LC-MS/MS, allowed us to identify groups of PAs and their N-oxides, as well as identify the number of PAs present in each group, including those that were not completely resolved chromatographically.

Chromatography, Liquid↗

PubMedDate not supplied

[Antifungal activity of aqueous extracts from the leaf of cowparsnip and comfrey].

We found that extracts from the leaves of medicinal comfrey and cowparsnip strongly inhibit the germination of Erysiphe graminis conidia and uredospores of Puccinia graminis. Spraying wheat seedlings with these extracts, in contrast to the irrigation of soil, markedly diminished infection in plants with powdery mildew. Antifungal activity in vitro and protective activity (when plants were sprayed) correlated with the level of phenolic compounds in these extracts. Experiments with healthy plants have demonstrated that the photosynthetic apparatus of wheat plants is stimulated by extracts. Spraying seedlings with the extracts resulted in an increased rate of O2 evolution calculated per unit of chlorophyll, an increase in the ratio (FM-FT)/FT in the experiments that recorded slow fluorescence induction, an increase in the relative light intensity of band A, and a decrease of relative intensity of band C in experiments with thermoluminescence of wheat leaves. These results provide evidence that the protective activity of comfrey and cowparsnip extracts is associated with their action on the pathogenic fungus and with the activation of natural defense reactions of the host plant.

Antifungal Agents↗

PubMedDate not supplied

Investigation of pyrrolizidine alkaloids and their N-oxides in commercial comfrey-containing products and botanical materials by liquid chromatography electrospray ionization mass spectrometry.

Pyrrolizidine alkaloids (PAs) and their N-oxides are found in several plant families throughout the world. PAs are potentially toxic to the liver and/or lungs in humans and may cause acute liver failure, cirrhosis, pneumonitis, or pulmonary hypertension. PAs are also carcinogenic to animals, and they have been linked to the development of hepatocellular and skin squamous cell carcinomas as well as liver angiosarcomas. According to experimental studies, the quantity of PAs in some herbal teas and dietary supplements is sufficient to be carcinogenic in exposed individuals. A method for the extraction and identification of PAs and their N-oxides in botanical materials and commercial comfrey-containing products has been developed using liquid chromatography electrospray ionization mass spectrometry. Following optimization of the extraction procedure and the chromatographic conditions, the method was applied to the analysis of 10 herbal remedies. All of the products that were labeled to contain comfrey were found to contain measurable quantities of PAs.

Alkaloids↗

PubMed1991

The effects of comfrey derived pyrrolizidine alkaloids on rat liver.

Three groups of young adult rats were fed pyrrolizidine alkaloids derived from Russian comfrey to study the effects of the herb on the liver. Group I animals received a single dose of 200 mg/kg body wt, Group II 100 mg/kg three times a week for 3 weeks and Group III 50 mg/kg three times a week for 3 weeks. All rats showed light and electron-microscopic evidence of liver damage, the severity of which was dose dependent. There was swelling of hepatocytes and hemorrhagic necrosis of perivenular cells. There was a concomitant loss of sinusoidal lining cells with disruption of sinusoidal wall and the sinusoids were filled with cellular debris, hepatocyte organelles and red blood cells. Extravasation of red blood cells was evident. Terminal hepatic venules were narrowed by intimal proliferation, and in Group II and III, reiculin fibres radiated from these vessels. These appearances have been described in veno-occlusive disease due to pyrrolizidine alkaloids from other plant sources such as Senecio and Crotalaria. The safety of comfrey, a widely used herb, in relation to human consumption requires further investigation.

Animals↗

PubMed2006

Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: results of a double-blind, randomised, bicenter, placebo-controlled trial.

This randomised, double-blind, bicenter, placebo-controlled clinical trial investigated the effect of a daily application of 6g Kytta-Salbe f (3 x 2 g) over a 3 week period with patients suffering from painful osteoarthritis of the knee. The two hundred and twenty patients examined consisted of 153 women and 67 men of an average age of 57.9 years. On average, the complaints relating to osteoarthritis of the knee had persisted for 6.5 years. Two hundred and twenty patients were included in the Full Analysis Set (FAS) and safety collective, 186 (84.5%) in the Valid Case Analysis Set (VCAS) collective. In the course of the trial, the visual analog scale (VAS) total score (primary target value) in the verum group dropped by 51.6 mm (54.7%) and in the placebo group by 10.1 mm (10.7%). The average difference between the groups of 41.5 mm (95% confidence interval=34.8 to 48.2 mm) or 44.0% is significant (p<0.001). The significance is confirmed through the evaluation of the diary, the VCAS evaluation and the separate assessment of the two centres. This also applies to the separate assessment of the VAS total score following pain at rest and on movement. The WOMAC (Western Ontario and McMaster Universities) total score (secondary target value) also improved similar to the VAS total score. At the end of the trial, a reduction by 60.4 mm (58.0%) was recorded for the verum group and a reduction of 14.7 mm (14.1%) for the placebo group. The average group difference of 45.7 mm (95% confidence interval=37.1 to 54.3 mm) or 43.9% is significant (p<0.001). The difference between the treatment groups increased systematically and significantly, in parallel with the duration of the treatment. Thus, the superiority of the treatment with Kytta-Salbe f over that with the placebo is proven, even by means of the multi-factorial multivariate analysis for repetitive measurements. In respect of the explorative secondary target values SF-36 (quality of life), angle measurement (mobility of the knee), CGI (clinical global impression) and global assessment of efficacy by the physician and the patient, a significant superiority (p<0.001 each) of the verum group over the placebo group was also proven. The results suggest that the comfrey root extract ointment is well suited for the treatment of osteoarthritis of the knee. Pain is reduced, mobility of the knee improved and quality of life increased.

Administration, Cutaneous↗

PubMed1996

Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale).

Pyrrolizidine alkaloids have been linked to liver and lung cancers and a range of other deleterious effects. As with many natural toxicants, major problems arise in determining the effects of the different members of the class and the importance of various forms of ingestion. In this study we have investigated the levels of pyrrolizidine alkaloids in comfrey (Symphytum officinale), determined the levels in different parts of the plant and in herbal remedies, separated the alkaloids into two main groups--the principal parent alkaloids and the corresponding N-oxides--and, finally, carried out a simple bioassay based upon the mutagenic capability of the separated compounds in a human cell line. We conclude that the part of the plant ingested is important in terms of alkaloid challenge and that the effect of two of the major groups of alkaloids individually is different from that of alkaloids in the whole plant extract.

Base Sequence↗